The loss of thymic function with age may be due to diminished numbers of T-cell progenitors and the loss of critical mediators within the thymic microenvironment. To assess the molecular changes associated with this loss, we examined transcriptomes of progressively aging mouse thymi, of different sexes and on caloric-restricted (CR) vs. ad libitum (AL) diets. Genes involved in various biological and molecular processes including transcriptional regulators, stress response, inflammation and immune function significantly changed during thymic aging. These differences depended on variables such as sex and diet. Interestingly, many changes associated with thymic aging are either muted or almost completely reversed in mice on caloric-restricted diets. These studies provide valuable insight into the molecular mechanisms associated with thymic aging and emphasize the need to account for biological variables such as sex and diet when elucidating the genomic correlates that influence the molecular pathways responsible for thymic involution. Moreover, these results emphasize the need to account for biological variables such as sex and dietary interactions to elucidate the genomic correlates that influence the molecular pathways responsible for thymic involution. We are also currently completing the analysis and confirmation of these data from mice of various ages infused with various hormones that result in a partial restoration in thymocyte numbers. Array analysis of the thymi of such treated mice may yield valuable data on the common molecular processes involved in thymic regeneration. It is unclear whether certain lymphoid organs or cellular components play a critical role in longevity and lifespan. The overall goal of this project is to produce a comprehensive gene expression profile in the thymus, spleen, and lymph nodes during the aging process to identify unique and common genes and functionally related groups of genes that are expressed in age-dependent manner in these different organ systems. We have initially focused our efforts on the thymus, as its involution is believed to be one of the most significant obstacles to overcome in addressing the immunological deficits associated with aging.